title: Beclin 1 mitigates motor and neuropathological deficits in genetic mouse models of Machado-Joseph disease.
abstract: Machado-Joseph disease or spinocerebellar ataxia type 3, the most common dominantly-inherited spinocerebellar ataxia, results from translation of the polyglutamine-expanded and aggregation prone ataxin 3 protein. Clinical manifestations include cerebellar ataxia and pyramidal signs and there is no therapy to delay disease progression. Beclin 1, an autophagy-related protein and essential gene for cell survival, is decreased in several neurodegenerative disorders. This study aimed at evaluating if lentiviral-mediated beclin 1 overexpression would rescue motor and neuropathological impairments when administered to pre- and post-symptomatic lentiviral-based and transgenic mouse models of Machado-Joseph disease. Beclin 1-mediated significant improvements in motor coordination, balance and gait with beclin 1-treated mice equilibrating longer periods in the Rotarod and presenting longer and narrower footprints. Furthermore, in agreement with the improvements observed in motor function beclin 1 overexpression prevented neuronal dysfunction and neurodegeneration, decreasing formation of polyglutamine-expanded aggregates, preserving Purkinje cell arborization and immunoreactivity for neuronal markers. These data show that overexpression of beclin 1 in the mouse cerebellum is able to rescue and hinder the progression of motor deficits when administered to pre- and post-symptomatic stages of the disease.
authors.affiliation: Centre for Neuroscience and Cell Biology, University of Coimbra, 3004- 517 Coimbra, Portugal.
authors.forename: Isabel
authors.initials: I
authors.lastname: Nascimento-Ferreira
authors.forename: Clévio
authors.initials: C
authors.lastname: Nóbrega
authors.forename: Ana
authors.initials: A
authors.lastname: Vasconcelos-Ferreira
authors.forename: Isabel
authors.initials: I
authors.lastname: Onofre
authors.forename: David
authors.initials: D
authors.lastname: Albuquerque
authors.forename: Célia
authors.initials: C
authors.lastname: Aveleira
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Hirai
authors.forename: Nicole
authors.initials: N
authors.lastname: Déglon
authors.forename: Luís
authors.initials: L
authors.lastname: Pereira de Almeida
mesh_terms: D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use*; D000067699:Ataxin-3; D001343:Autophagy / Q000235:genetics; D000071186:Beclin-1; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D004195:Disease Models, Animal; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D017827:Machado-Joseph Disease / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009410:Nerve Degeneration / Q000209:etiology / Q000517:prevention & control; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000235:genetics; D004856:Postural Balance / Q000235:genetics; D011597:Psychomotor Performance / Q000502:physiology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D012678:Sensation Disorders / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D012097:Repressor Proteins; D049452:Green Fluorescent Proteins; C097188:polyglutamine; C092341:ATXN3 protein, human; D000067699:Ataxin-3
keywords: ataxin-3; autophagy; beclin-1, Machado-Joseph disease, spinocerebellar ataxia type 3